Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Risk of not being in employment, education or training (NEET) in late adolescence is signalled by school readiness measures at 4–5 years

Background Not being in employment, education, or training (NEET) is associated with poor health (physical and mental) and social exclusion. We investigated whether England’s statutory school readiness measure conducted at 4–5 years provides a risk signal for NEET in late adolescence. Methods We identified 8,118 individuals with school readiness measures at 4–5 years and NEET records at 16–17 years using Connected Bradford, a bank of linked routinely collected datasets. Children were categorised as ‘school ready’ if they reached a ‘Good Level of Development’ on the Early Years Foundation Stage Profile. We used probit regression and structural equation modelling to investigate the relationship between school readiness and NEET status and whether it primarily relates to academic attainment. Results School readiness was significantly associated with NEET status. A larger proportion of young people who were not school ready were later NEET (11%) compared to those who were school ready (4%). Most of this effect was attributable to shared relationships with academic attainment, but there was also a direct effect. Measures of deprivation and Special Educational Needs were also strong predictors of NEET status. Conclusions NEET risk factors occur early in life. School readiness measures could be used as early indicators of risk, with interventions targeted to prevent the long-term physical and mental health problems associated with NEET, especially in disadvantaged areas. Primary schools are therefore well placed to be public health partners in early intervention strategies

Comparative safety and health care expenditures among patients with chronic myeloid leukemia initiating first-line imatinib, dasatinib, or nilotinib

PURPOSE Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myeloid leukemia (CML). No overall survival differences were observed between patients initiating first- and second-generation TKIs in trials; however, real-world safety and cost outcomes are unclear. We evaluated comparative safety and health care expenditures between first-line imatinib, dasatinib, and nilotinib among patients with CML. PATIENTS AND METHODS Eligible patients had one or more fills for imatinib, dasatinib, or nilotinib in the MarketScan Commercial and Medicare Supplemental databases between January 1, 2011, and December 31, 2016 (earliest fill is the index date), 6 months pre-index continuous enrollment, CML diagnosis, and no TKI use in the pre-index period. Hospitalizations or emergency department visits (safety events) were compared across treatment groups using propensity-score-weighted 1-year relative risks (RRs) and subdistribution hazard ratios (HRs). Inflation-adjusted annual health care expenditures were compared using quantile regression. RESULTS Eligible patients included 1,417 receiving imatinib, 1,067 receiving dasatinib, and 647 receiving nilotinib. The 1-year risk of safety events was high: imatinib, 37%; dasatinib, 44%; and nilotinib, 40%, with higher risks among patients receiving dasatinib (RR, 1.17; 95% CI, 1.06 to 1.30) and nilotinib (RR, 1.07; 95% CI, 0.93 to 1.23) compared with those receiving imatinib. Over a median of 1.7 years, the cumulative incidence of safety events was higher among patients receiving dasatinib (HR, 1.23; 95% CI, 1.10 to 1.38) and nilotinib (HR, 1.08; 95% CI, 0.95 to 1.24) than among those receiving imatinib. One-year health care expenditures were high (median, $125,987) and were significantly higher among patients initiating second-generation TKIs compared with those receiving imatinib (difference in medians: dasatinib v imatinib,$22,393; 95% CI, $17,068 to$27,718; nilotinib v imatinib, $19,463; 95$14,689 to $24,236). CONCLUSION Patients receiving imatinib had the lowest risk of hospitalization or emergency department visits and 1-year health care expenditures. Given a lack of significant differences in overall survival, imatinib may represent the ideal first-line therapy for patients, on average

Phase fluctuations, dissipation and superfluid stiffness in d-wave superconductors

We study the effect of dissipation on quantum phase fluctuations in d-wave superconductors. Dissipation, arising from a nonzero low frequency optical conductivity which has been measured in experiments below $T_c$, has two effects: (1) a reduction of zero point phase fluctuations, and (2) a reduction of the temperature at which one crosses over to classical thermal fluctuations. For parameter values relevant to the cuprates, we show that the crossover temperature is still too large for classical phase fluctuations to play a significant role at low temperature. Quasiparticles are thus crucial in determining the linear temperature dependence of the in-plane superfluid stiffness. Thermal phase fluctuations become important at higher temperatures and play a role near $T_c$.Comment: Presentation improved, new references added (10 latex pages, 3 eps figures). submitted to PR

Improved and standardized method for assessing years lived with disability after burns and its application to estimate the non-fatal burden of disease of burn injuries in Australia, New Zealand and the Netherlands

Background: Burden of disease estimates are an important resource in public health. Currently, robust estimates are not available for the burn population. Our objectives are to adapt a refined methodology (INTEGRIS method) to burns and to apply this new INTEGRIS-burns method to estimate, and compare, the burden of disease of burn injuries in Australia, New Zealand and the Netherlands. Methods: Existing European and Western-Australian health-related quality of life (HRQL) datasets were combined to derive disability weights for three homogenous burn injury groups based on percentage total body surface area (%TBSA) burned. Subsequently, incidence data from Australia, New Zealand, and the Netherlands from 2010 to 2017 were used to compute annual non-fatal burden of disease estimates for each of these three countries. Non-fatal burden of disease was measured by years lived w

Tess hunt for young and maturing exoplanets (thyme). II. a 17 myr old transiting hot jupiter in the sco-cen association

We present the discovery of a transiting hot Jupiter orbiting HIP 67522 (T eff ∼ 5650 K; M ∗ ∼ 1.2M o˙) in the 10-20 Myr old Sco-Cen OB association. We identified the transits in the TESS data using our custom notch filter planet search pipeline and characterize the system with additional photometry from Spitzer; spectroscopy from SOAR/Goodman, SALT/HRS, LCOGT/NRES, and SMARTS/CHIRON; and speckle imaging from SOAR/HRCam. We model the photometry as a periodic Gaussian process with transits to account for stellar variability and find an orbital period of 6.9596+0.0000150-000016days and radius of10.02-0.53+0.54R⊕. We also identify a single transit of an additional candidate planet with radius 8.01-0.710.75R ⊕ that has an orbital period of ⪆23 days. The validated planet HIP 67522b is currently the youngest transiting hot Jupiter discovered and is an ideal candidate for transmission spectroscopy and radial velocity follow-up studies, while also demonstrating that some young giant planets either form in situ at small orbital radii or else migrate promptly from formation sites farther out in the disk

Pharmacological interventions for chronic pain in children:an overview of systematic reviews

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.</p

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-Type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs. awx326media1 5680039660001 The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.We thank the Medical Research Council (J.J.C., Career Development Award, G1100340), Wellcome Trust (200183/ Z/15/Z and 101054/Z/13/Z) and Arthritis Research UK (20200) for generous support and Shionogi for an academic research grant (165302). Thanks to the University of Siena for partially funding this research. J.T.B. is supported by a Research Fellowship from the Alzheimer�s Society. J.D.R. received funding from the Wellcome Trust through the London Pain Consortium and from Colciencias through a Francisco Jose de Caldas Scholarship (LASPAU, Harvard University). D.L.H.B. is a Wellcome senior clinical scientist (ref. no. 095698z/11/z and 202747/Z/16/Z) and member of the Wellcome Pain Consortium.Scopu

Search for Higgs bosons decaying to tautau pairs in ppbar collisions at sqrt(s) = 1.96 TeV

We present a search for the production of neutral Higgs bosons decaying into tautau pairs in ppbar collisions at a center-of-mass energy of 1.96 TeV. The data, corresponding to an integrated luminosity of 5.4 fb-1, were collected by the D0 experiment at the Fermilab Tevatron Collider. We set upper limits at the 95% C.L. on the product of production cross section and branching ratio for a scalar resonance decaying into tautau pairs, and we then interpret these limits as limits on the production of Higgs bosons in the minimal supersymmetric standard model (MSSM) and as constraints in the MSSM parameter space.Comment: 7 pages, 5 figures, submitted to PL